KR101932473B1 - Novel honokiol triazole conjugated compounds and pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient - Google Patents

Abstract

The present invention relates to a novel honokiol triazole conjugate compound in which a substituent including triazole in a hydroxyl group at a 2-position or a 4-position of honokiol is substituted, and a pharmaceutical composition for preventing or treating a cancer by including the same. According to an aspect of the present invention, the present invention provides the honokiol triazole conjugate compound shown by chemical formula 1 or the pharmaceutically acceptable salt. In chemical formula 1, R and R′ are individually and independently C6-C20 aryl or C3-C20 heteroaryl.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for preventing or treating cancer, and a pharmaceutical composition for the prevention or treatment of cancer comprising the same. [0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of a novel < RTI ID = 0.0 &

The present invention relates to a novel compound having a hydroxy group substituted with a substituent containing a triazole at position 2 or 4 of the honokiol, and a pharmaceutical composition for preventing or treating cancer comprising the same.

Cancer is a major disease that pose a threat to the lives of humankind, and cancer mortality is increasing every year. Although research to treat these cancers has been very active over the last few years, some methods have shown some therapeutic effect, but there is still no way to demonstrate a dramatic therapeutic effect.

Cancer treatments include surgery, radiation therapy, and chemotherapy. However, despite many treatments, cancer deaths continue to increase every year because existing therapies can temporarily inhibit cancer growth by removing the cancer with surgical procedures and administering radiation and chemotherapy , Invasion and metastasis from residual cancer cells after treatment resulted in a new malignant tumor in the unpredictable tissue, and as a result, these solid tumors were highly resistant to the anticancer drug, It is because life can not be saved.

In addition, in the case of chemotherapy, most of the chemicals used as anticancer drugs are mainly cytotoxic to normal cells as well as cancer cells. Therefore, many side effects are caused, and studies for developing anticancer drugs using natural products are actively conducted It is progressing.

On the other hand, 4-O-methylhornokiol was firstly isolated from Magnolia officinalis Rehd. Et Wils. In 1978. 4-O-methylhornokiol has antimicrobial effect together with magnolol, It is known that it has an insecticidal effect on larvae and brine shrimp, and Korean Patent Publication No. 2011-0037516, Korean Patent No. 10-932962 and No. 10-0926466, Korean Patent Publication No. 2009-94916, Korean Patent Publication No. 2008-104760 discloses 4-O-methyl honokiol extracted from the stem and leaves of Magnolia officinalis Rehd. Et Wils to treat colon or prostate cancer, to treat amyloid-related diseases, to prevent hair loss, And can be used for skin whitening.

However, in the past, only studies on 4-O-methylhornokiol have been reported, and it has been reported that a substituted compound containing a triazole in the hydroxyl group at position 2 or 4 of the honokiol, Usage has not yet been reported.

Korean Patent Publication No. 10-2011-0037516 Korean Patent No. 10-0932962 Korea Patent No. 10-0926466 Korea Patent Publication No. 2009-94916 Korea Patent Publication No. 2008-104760

 El-Feraly, F. S. et al., Lloydia, 41, p493, 1978

The inventors of the present invention have conducted studies to develop a therapeutic agent for cancer. As a result, the present inventors have found that a novel hornokioltriazole conjugate compound substituted with a substituent containing a triazole in the hydroxy group at the 2- or 4-position of the honokiol, And the toxicity in normal cells is remarkably lowered. Thus, the present invention has been completed.

It is therefore an object of the present invention to provide a novel hornokyotriazole conjugate compound or a pharmaceutically acceptable salt thereof.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating cancer comprising a novel hornokyotriazole conjugate compound or a pharmaceutically acceptable salt thereof as an active ingredient.

An aspect of the present invention provides a conjugated compound of the formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

이고, 나머지 하나는 수소, -(CH₂)_mCOR³ 또는

이고;One of R ¹ and R ² are

And the other is hydrogen, - (CH ₂ ) _m COR ³ or

ego;

R and R 'are each independently C6-C20 aryl or C3-C20 heteroaryl and wherein the aryl or heteroaryl of R may be further substituted with halogen, C1-C7 alkoxy, C6-C12 aryloxy, cyano or nitro Have;

R ³ is C ¹ -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR ⁴ R ⁵ ;

a, b, c and d are each independently an integer of 1 to 5;

m is an integer from 1 to 5;

R ⁴ and R ⁵ are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the above-mentioned honokyoltriazole conjugate compound or a pharmaceutically acceptable salt thereof as an active ingredient.

The inventive honokyol triazole conjugate compound is a novel structure compound in which a substituent containing a triazole is substituted for a hydroxy group at a position 2 or 4 of the honokiol.

In addition, the conjugated compound of the present invention exhibits low cytotoxicity and exhibits excellent inhibitory activity against cancer cells, particularly ovarian cancer cells, and thus can be effectively used for prevention or treatment of cancer.

Hereinafter, the present invention will be described in more detail. Unless otherwise defined, technical terms and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the following description, And a description of the known function and configuration will be omitted.

An aspect of the present invention provides a heterocyclic compound conjugate represented by the following formula:

[Chemical Formula 1]

In Formula 1,

이고, 나머지 하나는 수소, -(CH₂)_mCOR³ 또는

이고;One of R ¹ and R ² are

And the other is hydrogen, - (CH ₂ ) _m COR ³ or

ego;

R and R 'are each independently C6-C20 aryl or C3-C20 heteroaryl and wherein the aryl or heteroaryl of R may be further substituted with halogen, C1-C7 alkoxy, C6-C12 aryloxy, cyano or nitro Have;

R ³ is C ¹ -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR ⁴ R ⁵ ;

a, b, c and d are each independently an integer of 1 to 5;

m is an integer from 1 to 5;

R ⁴ and R ⁵ are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;

Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S;

The inventive conjugate compound of formula (I) according to the present invention is a novel compound having a substituent containing a triazole in the hydroxyl group at position 2 or 4 of the honokiol and is a novel compound having low cytotoxicity, It exhibits excellent inhibitory activity against ovarian cancer cells and can be effectively used as an effective ingredient for the prevention or treatment of cancer.

The term " alkyl " as used herein refers to a monovalent straight or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, examples of which include methyl, ethyl, Butyl, pentyl, hexyl, and the like.

The term " alkoxy ", as used herein, refers to a monovalent -O-alkyl radical which is linked to oxygen and alkyl, wherein alkyl is as defined above. Examples of such alkoxy atomic groups include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy and the like.

The term " aryl ", as used herein, refers to an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, with a single or fused ring containing, suitably 4-7, preferably 5 or 6 ring atoms in each ring A ring system, and a form in which a plurality of aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, indenyl, and the like.

The term " heteroaryl ", as used herein, refers to an aryl group wherein the remaining aromatic ring backbone atoms contain one to four heteroatoms selected from N, O, and S as aromatic ring backbone atoms, Monocyclic heteroaryl, and condensed polycyclic heteroaryl with one or more benzene rings, and may be partially saturated. The heteroaryl in the present invention also includes a form in which one or more heteroaryl is connected to a single bond. Examples of the heteroaryl group include pyrrole, indole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisoxazole, But are not limited to, benzothiophene, furan, benzofuran, and the like. The heteroaryl may have a carbon atom or a nitrogen atom in the ring as a bonding site.

The term " arylalkyl ", as used herein, refers to an alkyl group substituted with aromatic carbocyclic rings having one, two or three rings, including, but not limited to, benzyl.

The term " aryloxy ", as used herein, means a monovalent radical that is bound to oxygen and aryl, where " aryl " is as defined above. Examples of such aryloxy radicals include, but are not limited to, phenoxy, naphthoxy, and the like.

The term " arylalkyloxy ", as used herein, means a monovalent radical of an arylalkyl to which alkyl and oxygen are bonded, wherein the term " arylalkyl " is as defined above. Examples of such arylalkyloxy radicals include, but are not limited to, benzyloxy and the like.

In one embodiment of the present invention, the honokyol triazole conjugate compound may be selected from the compounds represented by the following general formulas (2) to (4).

(2)

(3)

[Chemical Formula 4]

In the above Chemical Formulas 2 to 4,

R and R 'are each independently C6-C20 aryl or C3-C20 heteroaryl, wherein the aryl or heteroaryl of R and R' may be further substituted with halogen, cyano or nitro;

R ¹ and R ² are each independently hydrogen or -CH ₂ COR ³ ;

R ³ is C ¹ -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy or hydroxy.

In one embodiment of the present invention, R and R 'are each independently selected from the group consisting of phenyl, naphthyl, biphenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, indolyl or benzoimide And R and R ' may be further substituted with halogen, cyano or nitro; R ¹ and R ² are each independently hydrogen or -CH ₂ COR ³ ; R ³ can be C ¹ -C 7 alkoxy or C 6 -C 12 aryloxy.

In one embodiment of the present invention, the honokyol triazole conjugate compound may be selected from the following structures, but is not limited thereto.

The above-described honokyol triazole conjugate compounds according to the present invention can be prepared by various methods based on known methods and / or techniques of organic synthesis, as will be described later, It is to be understood that the present invention is not limited to the above embodiments, but other methods may be present. For example, the compound of formula (1) can be synthesized by a click reaction of an alkene compound (A) with an azide compound (B, B ') as follows:

[Reaction Scheme 1]

[Reaction Scheme 2]

[Reaction Scheme 3]

In the above Reaction Schemes 1 to 3, Hal is halogen and R ¹ , R ² , R, R ', a, b, c and d are the same as defined in Formula 1.

In some cases, the reaction product can be separated and purified by a conventional method, for example, recrystallization and chromatography.

One preferred pharmaceutically acceptable form of the compound of formula (I) according to the present invention is a crystalline form including forms in pharmaceutical compositions.

The conjugated compound of formula (1) according to the present invention may form a hydrate or a solvate together with water or other organic solvent. Such hydrates or solvates are likewise included within the scope of the present invention. In the case of salts and solvates, the additional ion and solvent moieties should also be non-toxic. The compounds of the present invention may exist in different isoforms, and the present invention encompasses all such forms.

The novel honokyol triazole conjugate compound according to the present invention, a salt thereof, a solvate thereof, or a prodrug thereof exhibits excellent carcinogenic action.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer diseases, which comprises the above-mentioned honokyol triazole conjugate compound or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the cancer disease specifically includes ovarian cancer.

In one embodiment of the present invention, the pharmaceutically acceptable salt may be prepared by a conventional method in the art, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, Salts with inorganic acids such as hydrochloric acid, hydrobromic acid and carbonic acid, salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, Salts with organic acids such as acetylsalicylic acid (aspirin), salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline, Salts with sulfonic acids such as sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like, metal salts by reaction with alkali metals such as sodium and potassium, And the like salts.

In one embodiment of the present invention, the pharmaceutical composition comprises a conventional non-toxic pharmaceutically acceptable carrier, adjuvant, and excipient in the honokyoltriazole conjugate compound represented by Formula 1 or a pharmaceutically acceptable salt thereof And the like, and they can be manufactured into preparations for oral administration or parenteral administration preparations such as tablets, capsules, troches, liquids and suspensions which are customary in the pharmaceutical field and can be used for the treatment of the above-mentioned degenerative diseases .

In one embodiment of the present invention, excipients that can be used in the pharmaceutical composition include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, , Fragrances, and the like. Examples of suitable additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like. The ratios and properties of such excipients may be determined by the solubility and chemical properties of the selected tablet, the route of administration selected, and the standard pharmaceutical practice.

In one embodiment of the present invention, the dosage of the honokyol triazole conjugate compound represented by the formula (1) may be 0.01-1000 mg / kg / day for a total daily dose, This may vary depending on the patient's age, weight, sex, dosage form, health condition, and disease severity, and may be administered once or several times a day at certain intervals according to the judgment of a doctor or pharmacist.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the contents of the present invention are not limited by the following Examples.

[Preparation Example 1] Preparation of alkene compound A1

Hono kiol (3 g, 11.3 mmol) was dissolved in _{acetone, Cs 2 CO 3 (5.5 g} , 16.89 mmol), propargyl was added bromide (1.18 mL, 11.26 mmol) and KI (0.37 g, 2.25 mmol) at room temperature For 6 hours, and water was added to terminate the reaction. After work-up using dichloromethane (DCM), the obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 1: 9 v: v, Rf = 0.5) to obtain Compound A1 (260 mg, 8% yield).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 2.44 (t, J = 2.3Hz, 1H), 3.35 (d, J = 6.6Hz), 3.39 (d, J = 6.4Hz), 4.60 (s, 1H), J = 8.2 Hz, 1 H), 7.10 (m, 4H), 5.97 (m, 4H) ), 7.30 (m, 2H)

[Preparation Example 2] Preparation of alkyne compound A2

Hono kiol (3 g, 11.3 mmol) was dissolved in _{acetone, Cs 2 CO 3 (5.5 g} , 16.89 mmol), propargyl was added bromide (1.18 mL, 11.26 mmol) and KI (0.37 g, 2.25 mmol) at room temperature For 6 hours, and water was added to terminate the reaction. After work-up using dichloromethane (DCM), the obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (EA: HEX = 1: 9 v: v, Rf = 0.6) to give compound A2 (240 mg, 7% yield).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 2.49 (s, 1H), 3.35 (d, J = 6.68Hz), 3.44 (d, J = 6.36Hz), 4.83 (s, 2H), 5.01 (m, 4H ), 5.91 (m, 2H), 6.83 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H) ), 7.29 (s, IH), 7.38 (d, J = 8.4 Hz, IH)

[Preparation Example 3] Preparation of alkyne compound A3

Hono kiol (3 g, 11.3 mmol) was dissolved in _{acetone, Cs 2 CO 3 (5.5 g} , 16.89 mmol), propargyl was added bromide (1.18 mL, 11.26 mmol) and KI (0.37 g, 2.25 mmol) at room temperature For 6 hours, and water was added to terminate the reaction. After work-up using dichloromethane (DCM), the obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (EA: HEX = 1: 9 v: v, Rf = 0.7) to obtain Compound A3 (770 mg, 20% yield).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 2.46 (t, 1H), 2.51 (t, 1H), 3.37 (d, J = 6.8Hz), 3.45 (d, J = 6.8Hz), 4.73 (s, 2H 1H), 7.09 (s, 2H), 4.83 (s, 2H), 5.02 (d, J = 9.4 Hz, 2H), 5.08 3H), 7.27 (s, IH), 7.31 (d, J = 8.4 Hz, IH)

[Example 1] Production of Honokyol triazole conjugate compound 1

Compound Al (0.1 g, 0.33 mmol) was dissolved in acetone and benzyl azide (0.048 g, 0.36 mmol) and Cu (PPh ₃ ) ₃ Br (18 mg, 0.02 mmol) were added and reacted by microwave (Reaction condition: 75 DEG C, 1 hour). The solvent was removed using a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 4: 6 v / v) to obtain a conjugated compound 1 (white solid, 140 mg, 97% yield).

_{^{1 H NMR (CDCl 3, 400}} MHz) δ 3.22 (d, J = 6.4Hz, 2H), 3.32 (d, J = 6.4Hz, 2H), 4.97 (m, 4H), 5.09 (s, 2H), 5.59 (s, 2H), 5.93 (m, 2H), 6.77 (d, J = 8.4 Hz, 1H), 7.11 (m, 5H), 7.32 1H); ¹³ C NMR (CDCl ₃ , 100 MHz)? 34, 39, 54, 63, 113, 115.2, 115.6, 116, 112.6, 112.63, 125, 128 (2C), 128.8 , 131.2, 131.4, 133, 134, 136, 137, 145, 153.5, 153.6; ESI-MS: m / z [M + Na] < ⁺ > 460.2 (calcd.437.53)

[Example 2] Preparation of Honokyol triazole conjugate compound 2

Compound A2 (120 mg, 0.40 mmol) was dissolved in acetone and then 4-cyanobenzyl azide (75 mg, 0.47 mmol) and Cu (PPh ₃ ) ₃ Br (18 mg, 0.02 mmol) ) (Reaction condition: 80 DEG C, 0.5 hr). The solvent was removed by rotary evaporation and the residue was purified by silica column chromatography (EA: HEX = 4: 4 v / v) to give the honokioltriazole conjugate compound 2 (182 mg, 82% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.36 (d, J = 6.6Hz, 2H), 3.38 (d, J = 6.6Hz, 2H), 5.04 (m, 5H), 5.28 (s, 2H), 5.62 ( J = 8.1 Hz, 1H), 7.04 (m, 2H), 7.26 (m, 3H), 7.35 (d, 7.58 (s, 1 H), 7.68 (d, J = 8.4 Hz, 2 H)

[Example 3] Production of Honokyol triazole conjugate compound 3

Dissolving the compound A1 (0.12g, 0.39mmol) in acetone and then 4-cyanobenzyl azide (75 mg, 0.47mmol) and _{Cu (PPh 3) 3 Br (} 18mg, 0.02mmol) was added to a microwave (Microwave ) (Reaction condition: 80 DEG C, 0.5 hr). The solvent was removed by rotary evaporation and the residue was purified by silica column chromatography (EA: HEX = 4: 6 v / v) to give a conjugated compound 3 (white solid, 150 mg, 82% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.34 (d, J = 6.8Hz, 2H), 3.40 (d, J = 6.8Hz, 2H), 5.02 (m, 4H), 5.06 (s, 2H), 5.28 ( (m, 2H), 7.36 (m, 2H), 6.63 (s, 2H) = 8 Hz, 2H), 7.59 (s, IH), 7.69 (d, J = 8 Hz, 2H)

[Example 4] Preparation of Honokyol triazole conjugate compound 4

Compound A1 (120 mg, 0.4mmol) was dissolved in the acetone, 1- (2-O map ethyl) -2-methyl-5-nitro -1H- imidazole (186 mg, 0.55mmol) and Cu (PPh ₃ ) ₃ Br (24 mg, 0.04 mmol) was added and reacted with microwave (reaction condition: 70 ° C, 3 hours). The solvent was removed by rotary evaporation and the residue was purified by silica column chromatography (DCM: MeOH = 19: 1 v / v) to give the conjugated compound 4 (100 mg, 50% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 1.82 (s, 3H), 3.39 (d, J = 6.8Hz), 3.45 (d, J = 6.4Hz) 4.75 (s, 4H), 5.09 (m, 6H), J = 8 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 2 Hz, 8 Hz, 1H) 7.13 (s, 2H), 7.20 (s, 1H), 7.22 (ds, J = 2 Hz, 1H), 8.00 (s, 1H); _{^{13 C NMR (CDCl 3, 100MHz}} ) δ 13, 34, 39, 46, 49, 63, 114, 115.2, 115.7, 116, 123.2, 123.3, 125 (2C), 128, 128.8, 130, 131.3, 131.4, 133.4 , 133.7 (2C), 136, 137, 145, 153.3 (2C); ESI-MS: m / z [M + Na] < ⁺ > 523.2 (calcd. 500.55)

[Example 5] Preparation of Honokyol triazole conjugate compound 5

Compound A2 (120 mg, 0.4mmol) was dissolved in the acetone, 1- (2-O map ethyl) -2-methyl-5-nitro -1H- imidazole (186 mg, 0.55mmol) and Cu (PPh ₃ ) ₃ Br (24 mg, 0.04 mmol) was added and reacted with microwave (reaction condition: 85 ° C, 3 hours). The solvent was removed by rotary evaporation and the residue was purified by silica column chromatography (DCM: MeOH = 19: 1 v / v) to give the honokioltriazole conjugate compound 5 (75 mg, 38% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 1.66 (s, 3H), 3.37 (d, J = 7.6Hz), 3.38 (d, J = 7.2Hz), 4.67 (t, J = 5.6Hz, 2H), 4.81 (t, J = 6 Hz, 2H), 5.06 (m, 4H), 5.34 (s, 2H), 5.95 (m, 2H), 6.81 (d, J = 9.2 Hz, 1H), 6.95 (s, 1H), 6.99 (ds, J = 2 Hz, 1H), 7.04 (dd, J = 2 Hz, 8.4 Hz, 7.84 (s, 1 H); ¹³ C NMR (CDCl ₃ , 100 MHz)? 12,34,39,46,49,60,111,115.4,115.5,116,123.45,123.49,128.2,128.3,128,129,131,131.2,131.4,131.7, 132, 136, 137, 145, 150, 151, 153; ESI-MS: m / z [M + Na] < ⁺ > 523.2 (calcd. 500.55)

[Example 6] Preparation of Honokyol triazole conjugate compound 6

Compound (Al) (130 mg, 0.42 mmol) was dissolved in acetone, then tryptamine azide (95 mg, 0.51 mmol) and Cu (PPh ₃ ) ₃ Br (24 mg, 0.02 mmol) (Reaction condition: 85 ° C, 3 hours). The solvent was removed by a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain a conjugated compound 6 mg, 64% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.27 (t, J = 6.4Hz, 2H), 3.37 (d, J = 7.2Hz, 2H), 3.39 (d, J = 7.2Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 5.09 (m, 6H), 5.64 (s, IH), 5.98 (m, 2H), 6.50 (ds, ), 6.95 (m, 2H), 7.06 (dd, J = 2 Hz, 8 Hz, 1H), 7.12 (m, 2H), 7.19 , J = 8 Hz, 1 H), 7.83 (s, 1 H)

[Example 7] Preparation of Honokyol triazole conjugate compound 7

Compound (Al) (130 mg, 0.42 mmol) was dissolved in acetone, then tryptamine azide (95 mg, 0.51 mmol) and Cu (PPh ₃ ) ₃ Br (24 mg, 0.02 mmol) (Reaction condition: 85 ° C, 3 hours). The solvent was removed using a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain a conjugated compound 7 mg, 87% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.33 (m, 6H), 4.64 (t, J = 6.4Hz, 2H), 5.04 (m, 4H), 5.19 (s, 2H), 5.60 (s, 1H), (M, 2H), 6.51 (ds, J = 1.6 Hz, 1H), 6.91 (d, J = 8 Hz, 2H), 7.04 (t, J = 7.2 Hz, 1H), 7.27 (m, 3H), 7.52 (d, J = 8 Hz,

[Example 8] Manufacture of honokiol triazole conjugate compound 8

Compound A1 (150 mg, 0.50mmol) was dissolved in the acetone, 1 (h map methyl) -3-chloro-benzene (100 mg, 0.60mmol) and _{Cu (PPh 3) 3 Br (} 23mg, 0.02mmol) to And the mixture was reacted with microwave (reaction condition: 80 ° C, 0.5 hr). The solvent was removed using a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain the honokyol triazole conjugate compound 8 mg, 81% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.36 (d, J = 6.96Hz), 3.38 (d, J = 6.68Hz) 5.11 (m, 6H), 5.29 (s, 1H), 5.44 (s, 2H), (M, 2H), 6.76 (d, J = 8.8 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 7.09 )

[Example 9] Preparation of Honokyol triazole conjugate compound 9

The compound A2 (150 mg, 0.50 mmol) was dissolved in acetone, and then 1- (azidomethyl) -3-chlorobenzene (100 mg, 0.60 mmol) and Cu (PPh ₃ ) ₃ Br (23 mg, 0.02 mmol) And the mixture was reacted with microwave (reaction condition: 80 ° C, 0.5 hr). The solvent was removed by a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain a Honokyol triazole conjugate compound 9 mg, 64% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.34 (d, J = 6.6Hz), 3.41 (d, J = 6.6Hz), 5.04 (m, 4H), 5.27 (s, 2H), 5.29 (s, 1H) , 5.53 (s, 2H), 5.95 (m, 2H), 6.89 (d, J = 8.2 Hz, 1H), 7.01 (ds, J = 2.1 Hz, 1H) J = 6.8 Hz, 1H), 7.23 (ds, J = 2.1 Hz, 1H), 7.30 (m, 4H), 7.54 (d, J = , 1H)

[Example 10] Preparation of Honokyol triazole conjugate compound 10

After the compound A2 (120 mg, 0.39 mmol) was dissolved in acetone, benzyl azide (60 mg, 0.43 mmol) and Cu (PPh ₃ ) ₃ Br (18 mg, 0.02 mmol) were added and reacted by microwave (Reaction condition: 80 ° C, 1 hour). The solvent was removed by rotary evaporation by silica column chromatography (EA: HEX = 1: 1 v / v → EA: HEX = 7: 3 v / v) to give the hono kiol triazole conjugate compound 10 (138 mg, 80% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.31 (d, J = 6.6Hz, 2H), 3.35 (d, J = 6.6Hz, 2H), 5.02 (m, 4H), 5.22 (s, 2H), 5.52 ( (dd, J = 2 Hz, 8.2 Hz, 1 H), 6.97 (d, J = 1.9 Hz, 7.03 (d, J = 8.4 Hz, 1H), 7.19 (ds, J = 2 Hz, 1H), 7.24 (m, 5H), 7.34 (m, 3H), 7.48 (s, 1H); ¹³ C NMR (CDCl ₃ , 100 MHz) 隆 34,39,54,62,112,195.5,115.7,115.9,112.66,112.69,127.1 128.1 (2C), 128.6,128.8,129.1 (2C) 130.4, 130.8, 131, 134, 136, 137, 144, 151, 155; ESI-MS: m / z [M + Na] < ⁺ > 460.2 (calcd.437.53)

[Example 11] Preparation of Honokyol triazole conjugate compound 11

Compound A2 (120 mg, 0.40mmol) was dissolved in the acetone, 1 (h map methyl) -3,4-dichlorobenzene (96 mg, 0.47 mmol) and _{Cu (PPh 3) 3 Br (} 18mg, 0.02mmol ) Was added and reacted with microwave (reaction condition: 80 ° C, 40 min). The solvent was removed by a rotary evaporator and then purified by silica column chromatography (EA: HEX = 1: 1 v / v to EA: HEX = 7: 3 v / v) to obtain a conjugated compound 11 mg, 85% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.32 (d, J = 6.6, 2H), 3.39 (d, J = 6.6Hz, 2H), 5.03 (m, 4H), 5.12 (s, 1H), 5.26 (s J = 8.1 Hz, 1 H), 7.02 (m, 3H), 7.09 (dd, J = 1.8 Hz, 8.2 Hz, 1H), 5.49 (s, 2H) ), 7.25 (m, 2H), 7.36 (ds, J = 1.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H)

[Example 12] Preparation of Honokyol triazole conjugate compound 12

Compound A1 (120 mg, 0.40mmol) was dissolved in the acetone, 1 (h map methyl) -3,4-dichlorobenzene (96 mg, 0.47 mmol) and _{Cu (PPh 3) 3 Br (} 18mg, 0.02mmol ) Was added and reacted with microwave (reaction condition: 80 ° C, 30 min). The solvent was removed by a rotary evaporator and then purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain the honokyol triazole conjugate compound 12 mg, 75% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.37 (m, 4H), 5.12 (m, 6H), 5.30 (s, 1H), 5.42 (s, 2H), 5.97 (m, 2H), 6.77 (d, J J = 8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 7.07 (m, 2H), 7.12 1.9 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 1 H)

[Example 13] Preparation of Honokyol triazole conjugate compound 13

Compound A2 (120 mg, 0.40mmol) was dissolved in the following, phenethyl azide (70 mg, 0.47mmol) and _{Cu (PPh 3) 3 Br (} 18mg, 0.02mmol) was added to a microwave reaction (Microwave) in acetone (Reaction condition: 80 < 0 > C, 40 min). The solvent was removed by a rotary evaporator, and the residue was purified by silica column chromatography (EA: HEX = 1: 1 v / v? EA: HEX = 7: 3 v / v) to obtain the honokioltriazole conjugate compound 13 mg, 79% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.22 (t, J = 7.1Hz, 2H), 3.34 (d, J = 6.6Hz, 2H), 3.38 (d, J = 6.6Hz, 2H), 4.62 (t, J = 7.1 Hz, 2H), 5.06 (m, 4H), 5.16 (s, IH), 5.23 (s, 2H), 5.94 m, 5 H), 7.27 (m, 6 H)

[Example 14] Preparation of Honokyol triazole conjugate compound 14

Compound A1 (120 mg, 0.40mmol) was dissolved in the following, phenethyl azide (70 mg, 0.47mmol) and _{Cu (PPh 3) 3 Br (} 18mg, 0.02mmol) was added to a microwave reaction (Microwave) in acetone (Reaction condition: 80 < 0 > C, 40 min). The solvent was removed by rotary evaporation by silica column chromatography (EA: HEX = 1: 1 v / v → EA: HEX = 7: 3 v / v) to give the hono kiol triazole conjugate compound 14 (90 mg, 51% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.17 (t, J = 7.3Hz, 2H), 3.36 (d, J = 6.2Hz, 2H), 3.43 (d, J = 6.7Hz, 2H), 4.53 (t, J = 7.2 Hz, 2H), 5.13 (m, 6H), 5.30 (s, IH), 6.60 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 7.06 (m, 4H), 7.12 (s, IH), 7.25 (m, 5H)

[Example 15] Preparation of Honokyol triazole conjugate compound 15

Compound 1 (0.07 g, 0.016 mmol) was dissolved in acetone and then CS ₂ CO ₃ (0.07 g, 0.021 mmol), TEA (0.067 mL, 0.048 mmol), methyl chloroacetate (0.02 mL, 0.021 mol) 0.005 g, 0.003 mmol) was added thereto and reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was worked up with water and dichloromethane (DCM), and the obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (DCM: MeOH = 19: 1 v: v) to give compound 15 (yellow liquid phase, 75 mg, 92.02% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.35 (d, J = 6.8Hz, 2H), 3.42 (d, J = 6.8Hz, 2H), 3.81 (s, 3H), 4.67 (s, 2H), 5.06 ( J = 8 Hz, 1 H), 7.00 (d, J = 8 Hz, 1 H), 5.17 (s,

[Example 16] Preparation of Honokyol triazole conjugate compound 16

Compound 10 (0.07 g, 0.016 mmol) was dissolved in acetone and then CS ₂ CO ₃ (0.07 g, 0.021 mmol), TEA (0.067 mL, 0.048 mmol), methyl chloroacetate (0.02 mL, 0.021 mol) 0.005 g, 0.003 mmol) was added thereto and reacted at room temperature for 24 hours. After completion of the reaction, the reaction mixture was worked up with water and dichloromethane (DCM), and the obtained organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The obtained residue was purified by silica column chromatography (DCM: MeOH = 19: 1 v: v) 16 (yellow liquid phase, 94.7 mg, 99% yield).

_{^{1 H NMR (CDCl 3, 400MHz}} ) δ 3.36 (d, J = 6.8Hz, 2H), 3.39 (d, J = 6.8Hz, 2H), 3.76 (s, 3H), 4.55 (s, 2H), 5.02 ( J = 8.4 Hz, 1H), 7.06 (dd, J = 2 Hz, 1H), 5.55 (s, 2H), 5.96 1H), 7.13 (ds, J = 2 Hz, 1H), 7.29 (m, 2H), 7.38

[ Experimental Example  1] Measurement of anticancer effect

To determine the anticancer activity of the honokyol triazole conjugate compounds prepared in Examples 1 to 14, cytotoxicity against human cancer cells was measured. The cancer cells used were A2780 (ovarian cancer) and OVCAR3 (ovarian cancer).

First, the cancer cells were cultured in a 5% CO ₂ thermostatic chamber at 37 ° C., and 10% fetal bovine serum (FBS) was added thereto using RPMI 1640 as a base medium.

In order to confirm the cytotoxicity of the inventive honokyol triazole conjugate compound, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) Experiments were performed [Armichael et al., Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemisensitivity testing. Cancer Research, 47, pp. 944-946, 1987]. MTT assays are based on the principle that the soluble tetrazolium salt MTT (yellow) is reduced to formazan crystals (purple) by the dehydrogenase action of mitochondria in living cells, The greater the number of crystals of formazan crystals, the higher the absorbance is measured.

Each of the cultured cancer cells was inoculated into a 96-well plate (5 × 10 ⁴ cells / well) and cultured in 100 μl of RPMI medium containing 5% FBS for 24 hours. 50 μl of MTT solution (5.0 μg / ml) was added to each well and incubated for an additional 4 hours, after which the supernatant of the plate was added And the formazan blue crystals in the cells produced by MTT were dissolved in 100 μl of DMSO to dissolve the precipitate and analyzed by ELISA analyzer (Perkin Elmer Cetus, Foster City, Ca, USA) at a wavelength of 540 nm The viable cell number was measured by measuring the absorbance of each well in the wells. When the absorbance of the well containing no cells is 0% and the absorbance of the well not containing the hornokyol triazole conjugate compound of the present invention is 100%, the concentration showing 50% absorbance, that is, 50% The inhibitory concentrations IC ₅₀ values were calculated and are shown in Table 1 below.

Cytotoxicity IC ₅₀ (μM) Ovarian cancer cell A2780 OVCAR3 Compound 1 14.3 ± 1.4 37.2 ± 2.1 Compound 2 14.1 ± 1.7 > 200 Compound 3 10.5 ± 1.0 21.5 ± 1.5 Compound 4 19.2 ± 0.9 32.4 ± 2.2 Compound 5 14.4 ± 1.4 38.4 ± 1.0 Compound 6 7.8 ± 0.3 18.7 ± 1.3 Compound 7 19.7 ± 1.5 31.5 ± 0.0 Compound 8 9.1 ± 1.9 36.9 ± 2.0 Compound 9 8.9 ± 0.2 35.3 ± 1.5 Compound 10 6.2 ± 0.5 4.8 ± 0.6 Compound 11 15.0 ± 0.0 37.4 ± 0.9 Compound 12 10.0 ± 1.3 32.8 ± 0.2 Compound 13 10.0 ± 3.4 42.1 ± 0.9 Compound 14 11.9 ± 2.1 65.0 ± 0.4

As shown in the above Table 1, it can be seen that the honokyol triazole conjugate compound of the present invention has a strong cytotoxic activity against each ovarian cancer cell, showing strong anticancer activity. Accordingly, the anticancer agent using the honokyol triazole conjugate compound of the present invention can be very usefully used for the treatment of ovarian cancer.

Claims (5)

1. A honokyol triazole conjugate compound represented by the following formula (1).
[Chemical Formula 1]

In Formula 1,
One of R ¹ and R ² are

And the other is hydrogen, - (CH ₂ ) _m COR ³ or

ego;
R and R 'are each independently C6-C20 aryl or C3-C20 heteroaryl and wherein the aryl or heteroaryl of R may be further substituted with halogen, C1-C7 alkoxy, C6-C12 aryloxy, cyano or nitro Have;
R ³ is C ¹ -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy, hydroxy or -NR ⁴ R ⁵ ;
a, b, c and d are each independently an integer of 1 to 5;
m is an integer from 1 to 5;
R ⁴ and R ⁵ are each independently hydrogen, C 1 -C 7 alkyl or C 6 -C 12 aryl;
Wherein said heteroaryl comprises at least one heteroatom selected from N, O and S; The method according to claim 1,
Wherein the honokyol triazole conjugate compound is selected from the compounds represented by the following formulas (2) to (4).
(2)

(3)

[Chemical Formula 4]

In the above Chemical Formulas 2 to 4,
R and R 'are each independently C6-C20 aryl or C3-C20 heteroaryl, wherein the aryl or heteroaryl of R and R' may be further substituted with halogen, cyano or nitro;
R ¹ and R ² are each independently hydrogen or -CH ₂ COR ³ ;
R ³ is C ¹ -C 7 alkoxy, C 6 -C 12 aryloxy, C 6 -C 12 aryl C 1 -C 7 alkyloxy or hydroxy. The method according to claim 1,
The honokyol triazole conjugate compound is selected from the following structures.

A pharmaceutical composition for the treatment or prevention of cancer diseases, which comprises, as an active ingredient, a hornokyotriazole conjugate compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof. 5. The method of claim 4,
Wherein said cancer disease is ovarian cancer.